Use of copolymers as solubilizers for slightly water-soluble compounds

ABSTRACT

The use of copolymers obtained by free-radical polymerization of a mixture of
         i) 30 to 80% by weight of N-vinyllactam,   ii) 10 to 50% by weight of vinyl acetate, and   iii) 10 to 50% by weight of a polyether,
 
with the proviso that the total of components i), ii) and iii) equals 100% by weight,
 
as solubilizers for slightly water-soluble substances.

This application is a National Stage Application of PCT/EP2006/067747,filed Oct. 25, 2006 and claims priority to application DE102005053066.4, filed Nov. 4, 2005, the entire disclosures of which areincorporated herein by reference.

The present invention relates to the use of copolymers which areobtained by polymerizing vinyl acetate and N-vinyllactams in thepresence of a polyether as solubilizers for slightly water-solublesubstances, and to the corresponding preparations.

In the production of homogeneous preparations in particular of bioactivesubstances, solubilization of hydrophobic, i.e. slightly water-solublesubstances, has become of very great practical importance.

Solubilization means making substances which are slightly soluble orinsoluble in a particular solvent, especially water, soluble bysurface-active compounds, the solubilizers. Such solubilizers are ableto convert substances of low or zero solubility in water into clear, orat most opalescent, aqueous solutions without altering the chemicalstructure of these substances (cf. Römpp Chemie Lexikon, 9th edition,Vol. 5. p. 4203, Thieme Verlag, Stuttgart, 1992).

The produced solubilizates are characterized by the substance of low orzero solubility in water being in the form of a colloidal solution inthe aggregates of molecules of the surface-active compounds which formin aqueous solution, such as, for example, hydrophobic domains ormicells. The resulting solutions are stable or metastable single-phasesystems which appear optically clear or opalescent.

Solubilizers may for example improve the appearance of cosmeticformulations and of food preparations by making the formulationstransparent. In the case of pharmaceutical preparations, there mayadditionally be an increase in the bioavailability and thus the effectof drugs through the use of solubilizers.

The solubilizers employed for pharmaceutical drugs and cosmetic activesubstances are mainly surfactants such as ethoxylated castor oil orethoxylated hydrogenated castor oil, ethoxylated sorbitan fatty acidesters or ethoxylated hydroxystearic acid.

However, the solubilizers described above and employed to date show anumber of technical disadvantages when used.

The solubilizing effect of known solubilizers is only low for someslightly soluble drugs such as, for example, clotrimazole.

EP-A 876 819 describes the use of copolymers of at least 60% by weightof N-vinyl-pyrrolidone and amides or esters with long-chain alkylgroups.

EP-A 948 957 describes the use of copolymers of monoethylenicallyunsaturated carboxylic acids such as, for example, acrylic acid andhydrophobically modified comonomers such as, for example N-alkyl- orN,N-dialkylamides of unsaturated carboxylic acids with C₈-C₃₀-alkylradicals.

DE-A 199 350 63 discloses polyalkylene oxide-containing graft copolymersbased on vinyllactams and vinyl acetate, and the use thereof as gashydrate inhibitors.

EP-A 953 347 discloses the use of polyalkylene oxide-containing graftcopolymers as solubilizers. The graft copolymers described therein andcomposed of vinyl acetate and polyalkylene oxides are frequently notpowders but glutinous liquids, which is a technical disadvantage duringuse.

A further desirable requirement is for solubilizers to be able to formso-called “solid solutions” with slightly soluble substances. The term“solid solution” refers to a state in which a substance is in the formof a microdispersion or, in the ideal case, a molecular dispersion in asolid matrix, for example, a polymer matrix. Such solid solutionsresult, for example when used in the solid pharmaceutical dosage formsof a slightly soluble active ingredient, in an improved release of theactive ingredient. An important requirement is that such solid solutionsbe stable if stored even for a prolonged period, i.e. that the activeingredient does not crystallize out. Also important is the capacity ofthe solid solution, in other words the ability to form stable solidsolutions with maximum content of active ingredients.

An important part is played in the formation of solid solutions not onlyby the fundamental ability of the solubilizers to form solid solutionsbut also by the hygroscopicity of the solubilizers. Solubilizers whichabsorb too much water from the ambient air lead to liquefactions of thesolid solution and to unwanted crystallization of the activeingredients. A hygroscopicity which is too great may also cause problemsin processing to dosage forms.

Previously disclosed polymeric solubilizers have the disadvantage thatthey either do not form stable solid solutions. There is moreover roomfor improvement in relation to solubilization in aqueous systems. Someof the known solubilizers also have disadvantages in relation toprocessability because of their tendency to tackiness, because they donot represent sufficiently free-flowing powders.

The object therefore was to provide novel and improved solubilizers forapplications in pharmaceuticals, cosmetics, food technology,agricultural technology or other industries not having the describeddisadvantages.

The object has been achieved according to the invention by the use ofwater-soluble or water-dispersible copolymers which are obtained byfree-radical polymerization of a mixture of

-   -   i) 30 to 80% by weight of N-vinyllactam,    -   ii) 10 to 50% by weight of vinyl acetate and    -   iii) 10 to 50% by weight of a polyether,        with the proviso that the total of i), ii) and iii) equals 100%        by weight.

According to one embodiment of the invention, preferred polymers areobtained from:

-   -   i) 30 to 70% by weight of N-vinyllactam    -   ii) 15 to 35% by weight of vinyl acetate, and    -   iii) 15 to 35% by weight of a polyether,        and particularly preferred polymers from:    -   i) 40 to 60% by weight of N-vinyllactam    -   ii) 15 to 35% by weight of vinyl acetate    -   iii) 15 to 30% by weight of a polyether.

In a further embodiment of the invention, preferred polymers comprisefrom 10 to 35% by weight of a polyether.

Particularly preferred polymers are composed of

-   -   i) 40 to 60% by weight of N-vinyllactam    -   ii) 15 to 35% by weight of vinyl acetate    -   iii) 10 to 30% by weight of polyether.

The proviso that the total of components i), ii) and iii) equals 100% byweight also applies to the preferred and particularly preferredcompositions.

A suitable N-vinyllactam is N-vinylcaprolactam or N-vinylpyrrolidone ormixtures thereof. N-Vinylcaprolactam is preferably used.

Suitable and preferred polyethers are polyalkylene glycols. Thepolyalkylene glycols may have molecular weights of from 1000 to 100 000D [daltons], preferably 1500 to 35 000 D, particularly preferably 1500to 10 000 D. The molecular weights are determined on the basis of the OHnumber measured as specified in DIN 53240.

Polyethylene glycols are suitable and particularly preferredpolyalkylene glycols. Also suitable are polypropylene glycols,polytetrahydrofurans or polybutylene glycols which are obtained from2-ethyloxirane or 2,3-dimethyloxirane.

Suitable polyethers are also random or block copolymers of polyalkyleneglycols obtained from ethylene oxide, propylene oxide and butyleneoxides, such as, for example, polyethylene glycol-polypropylene glycolblock copolymers. The block copolymers may be of the AB or ABA type.

Preferred polyalkylene glycols also include those alkylated on one orboth terminal OH groups. Suitable alkyl radicals are branched orunbranched C₁- to C₂₂-alkyl radicals, preferably C₁-C₁₈-alkyl radicals,for example methyl, ethyl, n-butyl, isobutyl, pentyl, hexyl, octyl,nonyl, decyl, dodecyl, tridecyl or octadecyl radicals.

General processes for preparing the copolymers of the invention areknown per se. The preparation takes place by free-radicalpolymerization, preferably solution polymerization, in nonaqueousorganic solvents or in mixed nonaqueous/aqueous solvents.

Suitable nonaqueous organic solvents are, for example, alcohols such asmethanol, ethanol, n-propanol and isopropanol, and glycols such asethylene glycol and glycerol.

Further suitable solvents are esters such as, for example, ethylacetate, n-propyl acetate, isopropyl acetate, isobutyl acetate or butylacetate.

The polymerization is preferably carried out at temperatures from 60 to100° C.

Free-radical initiators are employed to initiate the polymerization. Theamounts of initiator or initiator mixtures used, based on monomeremployed, are between 0.01 and 10% by weight, preferably between 0.3 and5% by weight.

Depending on the nature of the solvent used, both organic and inorganicperoxides are suitable, such as sodium persulfate or azo initiators suchas azobisisobutyronitrile, azo-bis(2-amidopropane) dihydrochloride or2,2′-azobis(2-methylbutyronitrile).

Examples of peroxide initiators are dibenzoyl peroxide, diacetylperoxide, succinyl peroxide, tert-butyl perpivalate, tert-butylperethylhexanoate, tert-butyl perneodecanoate, tert-butyl permaleate,bis-(tert-butylper)cyclohexane, tert-butylperisopropyl carbonate,tert-butyl peracetate, 2,2-bis(tert-butylper)butane, dicumyl peroxide,di-tert-amyl peroxide, di-tert-butyl peroxide, p-menthane hydroperoxide,pinane hydroperoxide, cumene hydroperoxide, tert-butyl hydroperoxide,hydrogen peroxide and mixtures of said initiators. Said initiators canalso be used in combination with redox components such as ascorbic acid.

Particularly suitable initiators are tert-butyl perneodecanoate,tert-butyl perpivalate or tert-butyl perethylhexanoate.

The free-radical polymerization can place if appropriate in the presenceof emulsifiers, if appropriate further protective colloids, ifappropriate molecular weight regulators, if appropriate buffer systemsand if appropriate subsequent pH adjustment using bases or acids.

Suitable molecular weight regulators are sulfhydryl compounds such asalkyl mercaptans, e.g. n-dodecyl mercaptan, tert-dodecyl mercaptan,thioglycolic acid and esters thereof, mercaptoalkanols such asmercaptoethanol. Further suitable regulators are mentioned for examplein DE 197 12 247 A1, page 4. The necessary amount of the molecularweight regulators is in the range from 0 to 5% by weight based on theamount of (co)monomers to be polymerized. If regulators are used, theamount employed is in particular in the range from 0.05 to 2% by weight,particularly preferably 0.1 to 1.5% by weight. However, polymerizationin the absence of a regulator is very particularly preferred.

It is also possible if appropriate to use emulsifiers, for example ionicor nonionic surfactants whose HLB is normally in the range from 3 to 13.For the definition of HLB, reference is made to the publication by W. C.Griffin, J. Soc. Cosmetic Chem., Volume 5, 249 (1954). The amount ofsurfactants, based on the polymer can be from 0 to 10% by weight,preferably 0 to 5% by weight.

The monomer, or the monomer mixture or the emulsion of monomer(s) areintroduced together with the initiator, which is generally present insolution, into a stirred reactor at the polymerization temperature(batch process) or if appropriate metered continuously or in a pluralityof consecutive stages into the polymerization reactor (feed process). Itis usual in the feed process for the reactor to be charged, before thestart of the actual polymerization, besides the solvent (in order tomake stirring of the reaction mixture possible) also with partialquantities, rarely the total quantity intended for the polymerization,of the starting materials such as emulsifiers, protective colloids,monomers, regulators etc. or partial quantities of the feeds (generallymonomer feed or emulsion feed and initiator feed).

The polymerization can be carried out both under atmospheric pressureand in a closed reactor under elevated pressure. In this case it ispossible to polymerize either under the pressure set up during thereaction, or the pressure can be adjusted by injecting a gas orevacuating. The pressure can also be controlled by partial decompressionof the reactor into the condenser.

A nonaqueous solvent used for the polymerization can subsequently beremoved and replaced by water by steam distillation. This normallyentails initially the nonaqueous solvent being distilled out pure as faras possible and then being completely replaced by water by passing insteam.

After the polymerization it is possible to employ generally knownprocesses for reducing residual monomers. Examples of such processes arefurther addition of an initiator at the end of the polymerization,hydrolysis of vinyllactam monomers by adding acids, treatment of thepolymer solution with solid phases such as ion exchangers, feeding in amonomer which copolymerizes well, membrane filtration and furthercustomary methods.

The solids content of the resulting aqueous polymer dispersions orsolutions is usually from 10 to 70% by weight, preferably 15 to 60% byweight, particularly preferably 15 to 40% by weight.

The polymer dispersions or solutions can be converted into powder formor into granules by various drying processes such as, for example, spraydrying, fluidized spray drying, drum drying, paddle drying, belt dryingor freeze drying. It may be advisable during the spray drying to addadditives such as, for example, colloidal silica or hydrophobicallymodified colloidal silica.

The copolymers are obtained as aqueous dispersions or aqueous solutionsor, after removal of the water content, as very free-flowing,water-dispersible or water-soluble powders.

The polymers have Fikentscher K values in the range from 10 to 60,preferably 15 to 40, measured in a 1% by weight ethanolic solution.

Applications:

The copolymers to be used according to the invention can be employed inprinciple in all areas where substances of only low or zero solubilityin water are either intended to be employed in aqueous preparations orintended to display their effect in aqueous medium. The copolymers areaccordingly used as solubilizers for slightly water-soluble substances,in particular bioactive substances.

The term “slightly water-soluble” includes according to the inventionalso practically insoluble substances and means that at least 30 to 100g of water are required per g of substance for the substance todissolved in water at 20° C. In the case of practically insolublesubstances, at least 10 000 g of water are required per g of substance.

In the context of the present invention, slightly water-solublebioactive substances mean active pharmaceutical ingredients for humansand animals, cosmetic or agrochemical active substances or dietarysupplements or dietetic active substances.

Further slightly soluble substances suitable for solubilization are alsocolorants such as inorganic or organic pigments.

The present invention provides in particular amphiphilic compounds foruse as solubilizers for pharmaceutical and cosmetic preparations and forfood preparations. They have the property of solubilizing slightlysoluble active ingredients in the area of pharmacy and cosmetics,slightly soluble dietary supplements, for example vitamins andcarotenoids, but also slightly soluble active substances for use in cropprotection agents and veterinary medical active ingredients.

Solubilizers for Cosmetics:

The copolymers can be employed according to the invention assolubilizers in cosmetic formulations. They are suitable for example assolubilizers for cosmetic oils. They have a good solubilizing capacityfor fats and oils such as peanut oil, jojoba oil, coconut oil, almondoil, olive oil, palm oil, castor oil, soybean oil or wheatgerm oil orfor essential oils such as dwarf pine oil, lavender oil, rosemary oil,spruce needle oil, pine needle oil, eucalyptus oil, peppermint oil, sageoil, bergamot oil, terpentine oil, melissa oil, sage oil, juniper oil,lemon oil, anise oil, cardamom oil, peppermint oil, camphor oil etc. orfor mixtures of these oils.

The polymers of the invention can further be used as solubilizers for UVabsorbers which are slightly soluble or insoluble in water, such as, forexample, 2-hydroxy-4-methoxybenzophenone (Uvinul® M 40, from BASF),2,2′,4,4′-tetrahydroxy-benzophenone (Uvinul® D 50),2,2′-dihydroxy-4,4′-dimethoxybenzophenone (Uvinul® D49),2,4-dihydroxybenzophenone (Uvinul® 400), 2′-ethylhexyl2-cyano-3,3-diphenylacrylate (Uvinul® N 539),2,4,6-trianilino-p-(carbo-2′-ethylhexyl-1′-oxy)-1,3,5-triazine (Uvinul®T 150), 3-(4-methoxybenzylidene)camphor (Eusolex® 6300, from Merck),2-ethylhexyl N,N-dimethyl-4-aminobenzoate (Eusolex® 6007),3,3,5-trimethylcyclohexyl salicylate, 4-isopropyldibenzoylmethane(Eusolex® 8020), 2-ethylhexyl p-methoxycinnamate and 2-isoamylp-methoxycinnamate, and mixtures thereof.

The present invention therefore also relates to cosmetic preparationswhich comprise at least one of the copolymers of the invention havingthe composition stated at the outset as solubilizers. Preferredpreparations are those which, besides the solubilizer, comprise one ormore slightly soluble cosmetic active substances, for example theabovementioned oils or UV absorbers.

These formulations are water- or water/alcohol-based solubilizates. Thesolubilizers of the invention are employed in the ratio of from 0.2:1 to20:1, preferably 1:1 to 15:1, particularly preferably 2:1 to 12:1, tothe slightly cosmetic active substance.

The content of solubilizer of the invention in the cosmetic preparationis in the range from 1 to 50% by weight, preferably 3 to 40% by weight,particularly preferably 5 to 30% by weight, depending on the activesubstance.

It is possible in addition for further auxiliaries to be added to thisformulation, for example nonionic, cationic or anionic surfactants suchas alkyl polyglycosides, fatty alcohol sulfates, fatty alcoholethersulfates, alkanesulfonates, fatty alcohol ethoxylates, fattyalcohol phosphates, alkylbetaines, sorbitan esters, POE-sorbitan esters,sugar fatty acid esters, fatty acid polyglycerol esters, fatty acidpartial glycerides, fatty acid carboxylates, fatty alcoholsulfosuccinates, fatty acid sarcosinates, fatty acid isethionates, fattyacid taurinates, citric acid esters, silicone copolymers, fatty acidpolyglycol esters, fatty acid amides, fatty acid alkanolamides,quaternary ammonium compounds, alkylphenol ethoxylates, fatty aminoethoxylates, cosolvents such as ethylene glycol, propylene glycol,glycerol and others.

Further ingredients which may be added are natural or syntheticcompounds, e.g. lanolin derivatives, cholesterol derivatives, isopropylmyristate, isopropyl palmitate, electrolytes, colorants, preservatives,acids (e.g. lactic acid, citric acid).

These formulations are Used for example in bath additives such as bathoils, aftershaves, face tonics, hair tonics, eau de cologne, eau detoilette and in sunscreen compositions. A further area of use is theoral care sector, for example in mouthwashes, toothpastes, dentureadhesive creams and the like.

The copolymers are also suitable for industrial applications for examplefor preparations of slightly soluble coloring agents, in toners,preparations of magnetic pigments and the like.

Description of the Solubilization Method:

The copolymers of the invention can be employed for preparingsolubilizates for cosmetic formulations either as 100% pure substanceor, preferably, as aqueous solution.

Normally, the solubilizers will be dissolved in water and vigorouslymixed with the slightly soluble cosmetic active substance to be used ineach case.

However, it is also possible for the solubilizer to be mixed vigorouslywith the slightly soluble cosmetic active substance to be used in eachcase and then for demineralized water to be added while stirringcontinuously.

Solubilizers for Pharmaceutical Applications:

The claimed copolymers are likewise suitable for use as solubilizer inpharmaceutical preparations of any type which may comprise one or moredrugs which are slightly soluble or insoluble in wafer, and vitaminsand/or carotenoids. Aqueous solutions or solubilizates for oraladministration are of particular interest in this connection. Thus, theclaimed copolymers are suitable for use in oral dosage forms such astablets, capsules, powders, solutions. In these they may increase thebioavailability of the slightly soluble drug. Solid solutions of activeingredient and solubilizer are used in particular.

It is possible to employ for parenteral administration besidessolubilizers also emulsions, for example fatty emulsions. The claimedcopolymers are also suitable for processing a slightly soluble drug forthis purpose.

Pharmaceutical formulations of the abovementioned type can be obtainedby processing the claimed copolymers with active pharmaceuticalingredients by conventional methods and with use of known and novelactive ingredients.

The application of the invention may additionally comprisepharmaceutical excipients and/or diluents. Excipients which areparticularly mentioned are cosolvents, stabilizers, preservatives.

The active pharmaceutical ingredients used are insoluble or sparinglysoluble in water. According to DAB 9 (German Pharmacopeia), thesolubility of active pharmaceutical ingredients is categorized asfollows: sparingly soluble (soluble in 30 to 100 parts of solvent);slightly soluble (soluble in 100 to 1000 parts of solvent); practicallyinsoluble (soluble in more than 10 000 parts of solvent). The activeingredients may in this connection come from any range of indications.

Examples which may be mentioned here are benzodiazepines,antihypertensives, vitamins, cytostatics—especially Taxol, anesthetics,neuroleptics, antidepressants, agents having antiviral activity, suchas, for example, agents having anti-HIV activity, antibiotics,antimycotics, antidementia agents, fungicides, chemotherapeutics,urologicals, platelet aggregation inhibitors, sulfonamides,spasmolytics, hormones, immunoglobulins, sera, thyroid therapeutics,psychoactive drugs, antiparkinson agents and other antihyperkinetics,opthalmologicals, neuropathy products, calcium metabolism regulators,muscle relaxants, anesthetics, lipid-lowering agents,hepatotherapeutics, coronary agents, cardiac agents, immunotherapeutics,regulatory peptides and their inhibitors, hypnotics, sedatives,gynecologicals, gout remedies, fibrinolytics, enzyme products andtransport proteins, enzyme inhibitors, emetics, blood flow stimulators,diuretics, diagnostic aids, corticoids, cholinergics, biliarytherapeutics, anti asthmatics, bronchodilators, beta-receptor blockers,calcium antagonists, ACE inhibitors, arteriosclerosis remedies,antiinflammatory drugs, anticoagulants, antihypertensives,antihypoglycemics, antihypertensives, antifibrinolytics, antiepileptics,antiemetics, antidotes, antidiabetics, antiarrhythmics, antianemics,antiallergics, anthelmintics, analgesics, analeptics, aldosteroneantagonists, slimming agents.

One possible production variant is to dissolve the solubilizer in theaqueous phase, if appropriate with gentle heating, and subsequently todissolve the active ingredient in the aqueous solubilizer solution. Itis likewise possible to dissolve solubilizer and active ingredientsimultaneously in the aqueous phase.

It is also possible to use the copolymers of the invention assolubilizer for example by dispersing the active ingredient in thesolubilizer, if appropriate with heating, and mixing with water whilestirring.

A further possibility is for the solubilizers to be processed in themelt with the active ingredients. It is possible in this way inparticular to obtain solid solutions. Also suitable for this purpose isthe melt extrusion process, inter alia. A further possibility forproducing solid solutions is also to prepare solutions of solubilizerand active ingredient in suitable organic solvents and subsequently toremove the solvent by usual processes.

The invention therefore also relates in general to pharmaceuticalpreparations which comprise at least one of the copolymers of theinvention as solubilizer. Preferred preparations are those which,besides the solubilizer, comprise an active pharmaceutical ingredientwhich is slightly soluble for insoluble in water, for example from theabovementioned areas of indication.

Particularly preferred pharmaceutical preparations from those mentionedabove are formulations which can be administered orally.

The content of solubilizer of the invention of the pharmaceuticalpreparation is in the range from 1 to 75% by weight, preferably 5 to 60%by weight, particularly preferably 5 to 50% by weight, depending on theactive ingredient.

A further particularly preferred embodiment relates to pharmaceuticalpreparations in which the active ingredients and the solubilizer arepresent as solid solution. In this case, the ratio of solubilizers toactive ingredient is preferably from 1:1 to 4:1 by weight, but may be upto 100:1, in particular up to 15:1. The only concerns are that when thefinished drug form is used firstly the amount of active ingredientpresent in the drug form is effective, and secondly the forms are nottoo large in the case of oral drug forms.

Solubilizers for Food Preparations:

Besides use in cosmetics and pharmacy, the copolymers of the inventionare also suitable as solubilizers in the food sector for nutritionalsubstances, auxiliaries or additives which are slightly soluble orinsoluble in water, such as, for example, fat-soluble vitamins orcarotenoids. Examples which may be mentioned are beverages colored withcarotenoids.

Solubilizers for Crop Protection Preparations:

Use of the copolymers of the invention as solubilizers in agrochemistrymay comprise inter alia formulations which comprise pesticides,herbicides, fungicides or insecticides, especially includingpreparations of crop protection agents employed as formulations forspraying or watering.

The copolymers of the invention are distinguished by a particularly goodsolubilizing effect. They are also able to form so-called solidsolutions with slightly soluble substances. Solid solutions referaccording to the invention to systems in which no portions of theslightly soluble substance are evidently crystalline on visualinspection. There are furthermore no evidently amorphous constituents onvisual inspection of the stable solid solutions. The visual inspectiontakes place using a light microscope at 40× magnification.

The preparation and use of the copolymers of the invention is explainedin more detail in the following examples.

Preparation of the Copolymers

Abbreviations Used:

-   VCap: N-vinylcaprolactam-   VP: N-vinylpyrrolidone-   VAc: vinyl acetate-   PEG: polyethylene glycol

EXAMPLE 1

Initial charge: 165.0 g of ethyl acetate, 100.0 g of PEG 6000, 20.0 g ofvinyl acetate, 10.50 g of feed 2 Feed 1: 500 g of vinylcaprolactam 180 gof vinyl acetate 100 g of ethyl acetate Feed 2: 10.50 g of tert-butylperethylhexanoate (98% by weight pure) 94.50 g of ethyl acetate

The initial charge was heated in a stirred apparatus without the portionof feed 2 under an N₂ atmosphere to 77° C. When the internal temperatureof 77° C. was reached, the portion of feed 2 was added and initialpolymerization was carried out for 15 min. Subsequently, feed 1 wasmetered in over the course of 5 h and feed 2 over the course of 2 h.After all the feeds had been metered in, the reaction mixture waspolymerized for a further 3 h. After the further polymerization, thereaction mixture was diluted with 500 ml of water. Volatile constituentswere removed by steam distillation. The aqueous solution was freezedried. The copolymers were obtained after grinding as very free-flowingpowders.

The further copolymers of examples 2-5 were prepared analogously withslightly modified composition.

EXAMPLE 2

Initial charge: 165 g of ethyl acetate 100.0 g of PEG 6000 22.0 g ofvinyl acetate 10.50 g of feed 2 Feed 1: 480 g of vinylcaprolactam 198 gof vinyl acetate 100 g of ethyl acetate Feed 2: 10.50 g of tert-butylperethylhexanoate (98% by weight pure) 94.50 g of ethyl acetate

EXAMPLE 3

Initial charge: 25 g of ethyl acetate 104.0 g of PEG 6000, 1.0 g of feed2 Feed 1: 240 g of vinyl acetate Feed 2: 456 g of vinylcaprolactam 240 gof ethyl acetate Feed 3: 10.44 g of tert-butyl perpivalate (75% byweight pure in a mixture of aliphatics) 67.90 g of ethyl acetate

EXAMPLE 4

Initial charge: 25 g of ethyl acetate 112.0 g of PEG 6000, 1.0 g of feed2 Feed 1: 408 g of vinylcaprolactam 280 g of vinyl acetate 240 g ofethyl acetate Feed 2: 10.32 g of tert-butyl perpivalate (75% by weightpure in a mixture of aliphatics) 67.10 g of ethyl acetate

EXAMPLE 5

Initial charge: 25 g of ethyl acetate, 112.0 g of PEG 6000, 1.0 g offeed 2 Feed 1: 428.0 g of vinylcaprolactam 260.0 g of vinyl acetate 240g of ethyl acetate Feed 2: 10.32 g of tert-butyl perpivalate (75% byweight pure in a mixture of aliphatics) 67.10 g of ethyl acetate

Composition in % by weight K value PEG (1% by weight in Example No. 6000VCap VAc ethanol) 1 12.5 62.5 25 18.5 2 12.5 60 27.5 40.4 3 13 57 3019.8 4 14 51 35 25.2 5 14 53.5 32.5 22.4

EXAMPLE 6

Initial charge: 50 g of butyl acetate, 150.0 g of PEG 6000, 1.0 g offeed 3 Feed 1: 500 g of VCap, 120.0 g of butyl acetate Feed 2: 350.0 gof VAc, 80.0 g of butyl acetate Feed 3: 12.75 g of tert-butylperpivalate (75% by weight in aliphatic mixture), 117.25 g of butylacetate

The initial charge was heated in a stirred apparatus under an N₂atmosphere to 77° C. When the temperature was reached, feed 1, feed 2and feed 3 were started. Feed 1 was metered in over the course of 5 h,feed 2 was metered in over the course of 2 h and feed 3 was metered inover the course of 5.5 h. After all the feeds had been metered in, thereaction mixture was polymerized for a further 4 h. After the furtherpolymerization, the reaction mixture was diluted with 500 ml of solvent.Volatile constituents were removed by steam distillation. The aqueoussolution was freeze dried. The copolymers were obtained after grindingas very free-flowing powders.

The copolymers of Examples 7 to 17 were prepared analogously.

Composition in % by weight K value PEG (1% by weight Example No. 6000VCap VAc in ethanol) 6 15 50 35 32.2 7 20 50 30 21.7 8 25 50 25 22.7 930 50 20 23.6 10 35 50 15 25.1 11 50 40 10 24.3 Composition in % byweight K value PEG (1% by weight Example No. 1500 VCap VAc in ethanol)12 15 50 35 32.2 13 25 50 25 23.1 14 35 50 15 29.7 K value (1% by weightExample No. Composition in % by weight in ethanol) 15 PEG VCap VAc 30.59000 50 35 15 16 PEG VP VAc 35.6 1500 60 20 20 17 PEG VP VAc 35.8 600060 20 20

EXAMPLE 18

Initial charge: 40 g of ethyl acetate, 120.0 g of PEG 6000, 1.28 g offeed 2 Feed 1: 400 g of VCap, 280.0 g of vinyl acetate, 225.0 g of ethylacetate Feed 2: 10.2 g of tert-butyl perpivalate (75% by weight pure inmixture of aliphatics), 118.4 g of ethyl acetate

The initial charge was heated in a stirred apparatus under an N₂atmosphere to 77° C. When the temperature was reached, the feeds werestarted. Feed 1 was metered in over the course of 5 h and feed 2 overthe course of 5.5 h. After all the feeds had been metered in, thereaction mixture was polymerized for a further 3 h. After the furtherpolymerization, the reaction mixture was diluted with about 500 ml ofsolvent. Volatile constituents were removed by steam distillation. Theaqueous solution was freeze dried. The copolymers were obtained aftergrinding as very free-flowing powders.

EXAMPLE 19

Analogous to example 18, but with tert-butyl perethylhexanoate at a bathtemperature of 85° C.

EXAMPLE 20

Analogous to example 19, but with the following feeds:

Initial charge: 120.0 g of PEG 6000 Feed 1: 160 g of VCap, 280.0 g ofvinyl acetate, 50.0 g of ethyl acetate Feed 2: 10.2 g of tert-butylperpivalate (75% by weight pure in mixture of aliphatics), 91.80 g ofethyl acetate Feed 3: 240 g of VCap, 242.0 g of ethyl acetate Feed 1 wasadded over the course of 2 h and feed 2 over the course of 5.5 h. Feed 3was started immediately after the end of feed 1.

EXAMPLE 21

Analogous to example 19, monomer composition in % by weight: 15 PEG/55VCap/30 Vac.

EXAMPLE 22

Analogous to example 19, with tert-butanol as solvent.

EXAMPLE 23

Analogous to example 18, after the end of the further polymerization9.07 g of tert-butyl perpivalate in 81.6 g of ethyl acetate were added,followed by further polymerization for 2 h to reduce residual monomers.

EXAMPLE 24

Analogous to example 21, but with monomer composition in % by weight: 15PEG/50 VCap/35 VAc, doubled quantities and in a pressure apparatus at90° C. A pressure in the region of 0.2 MPa was set up in this case.

EXAMPLE 25 Spray Drying

A polymer prepared in analogy to example 18 was spray dried. The dryingtook place straightforwardly.

Atomizer: two-fluid nozzle, 1.3 mm Teflon Additive: none Solids content:15% by weight Inlet temp.: 121° C. Outlet temp.: 55° C. Yield: 77%Color: white Powder property: slightly blocked

Addition of colloidal silica as spraying aid (additive) improved thealready good properties and afforded a free-flowing powder.

EXAMPLE 26

An aqueous polymer solution obtained as in example 1 was processed byspray drying in analogy to example 25.

COMPARATIVE EXAMPLES

For comparison, the graft copolymers described in EP-A 953 437 (Examples1, 3; Table 1) of the following composition were prepared:

Comparative Example A

-   70% by weight of VAc, 30% by weight of PEG 6000

Comparative Example B

-   70% by weight of VAc, 30% by weight of PEG 1500    These polymers exhibited noticeable tackiness.    Preparation of Solid Solutions: General Procedure

The polymer-active ingredient mixture was produced by weighing theactive ingredient and the polymer in the ratio 1:1 by weight into asuitable glass vessel (2 g of each) and then adding 16 ml ofdimethylformamide as solvent. The mixture was stirred with a magneticstirrer at 20° C. for 24 hours. The solution was then applied to a glassplate using a 120 μm knife. This plate was dried under a hood at RT for0.5 hour and then dried in a drying oven at 50° C. and 10 mbar for afurther 0.5 hour in order to remove the solvent quantitatively. Thesamples were subsequently inspected visually. If the films were clearand the active ingredient did not crystallize after 7 days, the activeingredient was assessed as stably dissolved in the polymer (indicationin Table 1:50). If no solid solution could be obtained with an activeingredient content of 50% by weight, the experiment was repeated with anactive ingredient loading of 33% by weight, and the formation of astable solid solution was assessed as above (indication in Table: 33).

Stability of a Solid Solution

Copolymer of Example No./Content of active ingredient [% by weight]Solid solution of 1/50 2/50 3/50 4/33 5/50 carbamazepine Copolymer ofExample No./Content of active ingredient [% by weight] Solid solution of1/50 2/50 3/50 4/50 estradiol Copolymer of Example No./Content of activeingredient [% by weight] Solid solution of 1/33 2/33 3/33 4/33 5/33piroxicam Copolymer of Example No./Solubilization at 20°C. in [g/100 ml]Solid solution of 1/50 2/50 3/50 4/33 5/50 clotrimazole Copolymer ofExample No./Content of active ingredient [% by weight] Solid solution of6/50 7/50 8/50 12/33 13/50 14/50 15/33 carbamazepine Copolymer ofExample No./Content of active ingredient [% by weight] Solid solution of6/50 7/50 8/50 9/50 10/50 12/50 14/50 15/33 estradiol Copolymer ofExample No./Content of active ingredient [% by weight] Solid solution of12/33 13/33 15/33 piroxicam Copolymer of Example No./Content of activeingredient [% by weight] Solid solution of 6 7/ 8/ 9/ 10/ 11/ 12/ 13/14/ 15/ 16/ clotrimazole 50 50 50 50 50 33 50 33 50 33 50 Copolymer ofExample No./Content of active ingredient [% by weight] Solid solution of18/50 19/50 20/50 21/33 22/50 24/50 carbamazepine Copolymer of ExampleNo./Content of active ingredient [% by weight] Solid solution of 18/5019/50 20/50 21/50 22/50 24/50 estradiol Copolymer of Example No./Contentof active ingredient [% by weight] Solid solution of 18/33 19/33 20/3321/33 22/33 24/33 piroxicam Copolymer of Example No./Content of activeingredient [% by weight] Solid solution of 18/50 19/50 20/50 21/33 22/5024/50 clotrimazole

No stable solid solutions were obtainable with the polymers ofComparative Examples A and B.

Preparation of Solubilizates

2 g of the copolymer were weighed into a glass beaker. A drug was thenweighed into each mixture in order to obtain a supersaturated solution,as follows. If the mass weighed in dissolved in the medium, the weightwas increased until a sediment formed. Amount of active ingredientweighed in: 17-β-estradiol 0.2 g; piroxicam 0.2; clotrimazole 0.2 g;carbamazepine 0.3 g; ketoconazole 0.25 g; griseofulvin 0.25 g;cinnarizine 0.25 g.

Phosphate buffer of pH 7.0 was then added until solubilizer andphosphate buffer were present in the ratio of 1:10 by weight. A magneticstirrer was used to stir this mixture at 20° C. for 72 hours. A restingperiod of at least 1 hour followed. The mixture was filtered and thenmeasured by photometry, and the content of active ingredient wasdetermined.

Copolymer of Ex. No./Solubilization at 20° C. in [g/100 ml]Carbamazepine 1/0.04 2/.07 3/0.40 4/0.28 5/0.26 Copolymer of Ex.No./Solubilization at 20° C. in [g/100 ml] Estradiol 1/0.05 3/0.234/0.33 5/0.25 Copolymer of Ex. No./Solubilization at 20° C. in [g/100ml] Piroxicam 1/0.11 2/0.18 3/0.28 4/0.09 5/0.13 Copolymer of Ex.No./Solubilization at 20° C. in [g/100 ml] Clotrimazole 1/0.01 2/0.013/0.17 4/0.15 Copolymer of Ex. No. /Solubilization at 20° C. in [g/100ml] Carbamazepine 6/ 7/ 8/ 9/ 10/ 11/ 12/ 13/ 14/ A/ B/ 0.31 0.35 0.220.22 0.19 0.19 0.26 0.12 0.17 0.10 0.11 Copolymer of Ex.No./Solubilization at 20° C. in [g/100 ml] Estradiol 6/0.23 7/0.188/0.17 9/0.09 10/0.09 14/0.04 A/0.07 B/0.11 Copolymer of Ex.No./Solubilization at 20° C. in [g/100 ml] Piroxicam 6/ 7/ 8/ 9/ 10/ 11/12/ 14/ 16/ 17/ A/ B/ 0.45 0.45 0.44 0.42 0.44 0.39 0.45 0.42 0.37 0.40.10 0.27 Copolymer of Ex. No./Solubilization at 20° C. in [g/100 ml]Clotrimazole 6/0.11 7/0.10 8/0.06 9/0.07 Copolymer of Ex.No./Solubilization at 20° C. in [g/100 ml] Carbamazepine 18/0.31 19/0.2520/0.28 21/0.27 Copolymer of Ex. No./Solubilization at 20° C. in [g/100ml] Estradiol 18/0.26 19/0.23 20/0.22 21/0.23 22/0.26 24/0.32 Copolymerof Ex. No./Solubilization at 20° C. in [g/100 ml] Piroxicam 18/0.1719/0.09 20/0.41 21/0.19 22/0.16 24/0.10 Copolymer of Ex.No./Solubilization at 20° C. in [g/100 ml] Clotrimazole 18/0.06 19/0.1320/0.18 21/0.12 22/0.13 Solubilization at 20° C. in [g/100 ml] Copolymerof Ex. 6 ketoconazole griseofulvin cinnarizine 0.11 0.31 0.02

The solubilization at 37° C. was determined in analogy to the methoddescribed above.

Copolymer of Ex. No./Solubilization at 37° C. in [g/100 ml]Carbamazepine 1/0.36 7/0.93 9/0.26 Copolymer of Ex. No./Solubilizationat 37° C. in [g/100 ml] Piroxicam 1/0.51 7/1.04 9/0.55 Copolymer of Ex.No./Solubilization at 37° C. in [g/100 ml] Estradiol 1/0.99 9/0.07Copolymer of Ex. No./Solubilization at 37° C. in [g/100 ml] Clotrimazole1/0.17

Determination of the Glass Transition Temperatures Tg as Measure of theTack-Free Processability:

Copolymer of Copolymer of Copolymer of T_(g)[°C.] Ex. 1 Comp. Ex. AComp. Ex. B +54 −32 −40

In addition, the release behavior of solid solutions of the inventioncomposed of solubilizer polymer and active ingredient (withcarbamazepine as example)—formulated in a tablet—was compared with therelease behavior of a tablet which comprises only active ingredientwithout solubilizer polymer. The following tablet compositions were usedfor this:

Formulation A: Solid Solution

Materials mg/Tablet [%] Solid solution 250 50 Microcrystalline cellulose230 46 Carboxymethylcellulose 15 3 sodium, crosslinked Colloidal silica2.5 0.5 Magnesium stearate 2.5 0.5 Total: 500 100Formulation B: Active Ingredient without Polymer (CBZ)

Materials mg/Tablet [%]t Carbamazepine 75 15 Lactose 175 35Microcrystalline cellulose 230 46 Carboxymethylcellulose 15 3 sodium,crosslinked Colloidal silica 2.5 0.5 Magnesium stearate 2.5 0.5 Total500 100

The solid solution was powdered in a mortar; the particle size was inthe region of 200 μm. The further excipients with the exception of themagnesium stearate are added as indicated in the table and mixed in aTurbula mixer for 10 minutes. The mass of magnesium stearate indicatedin the table is then added and mixed again in the Turbula mixer for 2minutes. The mixture was tableted in an EK 0 excentric press with a 12mm punch under a compressive force of 15 kN.

The release from the tablets was determined in 0.08 M HCl (300 ml) at22° C. Samples were filtered through a 10 μm filter and thecarbamazepine content was determined by UV spectrometry at 286 nm.

CBZ release Time [min] [%] Solid solution release [%] 0 0 0 10 96 20 4399 40 48 100 60 50 102 90 50 99 120 50 100

1. A method comprising solubilizing a slightly water soluble substancewith a copolymer wherein the copolymer solubilizes the slightlywater-soluble substance and wherein the copolymer is obtained byfree-radical polymerization of a mixture of i) 30 to 80% by weight ofN-vinylcaprolactam, N-vinylpyrrolidone, or a mixture thereof, ii) 10 to50% by weight of vinyl acetate, and iii) 10 to 50% by weight of apolyethylene glycol,
 1. with the proviso that the total of componentsi), ii) and iii) equals 100% by weight.
 2. The method according to claim1, where the copolymer is obtained from i) 30 to 70% by weight ofN-vinylcaprolactam, N-vinylpyrrolidone, or a mixture thereof, ii) 15 to35% by weight of vinyl acetate, and iii) 10 to 35% by weight of apolyethylene glycol.
 3. The method according to claim 1, whereN-vinylcaprolactam is employed as component i).
 4. The method accordingto claim 1, where the copolymer comprises a polyethylene glycol having amolecular weight of from 1000 daltons to 10 000 daltons as componentiii).
 5. The method according to claim 1, where the copolymer has a Kvalue from 10 to 60 and wherein the K value is measured in a 1% byweight ethanolic solution.
 6. The method according to claim 4, where thecopolymer has a K value of from 15 to 40 and wherein the K value ismeasured in a 1% by weight ethanolic solution.
 7. The method accordingto claim 1, where the slightly water-soluble substance is a bioactivesubstance.
 8. The method according to claim 1 for producing apharmaceutical preparation for the treatment of diseases.
 9. The methodaccording to claim 1 for producing cosmetic preparations.
 10. The methodaccording to claim 1 for producing-agrochemical preparations.
 11. Themethod according to claim 1 for producing-dietary supplements ordietetic compositions.
 12. The method according to claim 1 for producingfood products.
 13. The method according to claim 1 for producingcolorant preparations.